The present invention concerns methods of screening for Alzheimer""s disease susceptibility in subjects, along with methods of classifying susceptible individuals for treatment and methods of treating Alzheimer""s disease.
Alzheimer""s disease (AD) is marked by a devastating decrease in cognitive ability which is correlated with a decline in the number of synapses in the hippocampus and neocortex. One of the risk factors for development of AD is the gene coding for the E4 allele of a lipid carrier protein, apolipoprotein E (APOE, gene). The APOE E4 allele is a risk factor for late-onset, familial and sporadic AD while the APOE3 and E2 alleles are either neutral (E3) or protective (E2). Another risk factor is sex; both the incidence and prevalence of AD is greater in females than in males.
U.S. Pat. No. 5,508,167 to A. Roses et al., assigned to Duke University, discloses methods of diagnosing or prognosing Alzheimer""s disease in a subject. The methods involve directly or indirectly detecting the presence or absence of an apolipoprotein E type 4 (ApoE4) isoform or DNA, encoding ApoE4 in the subject. The presence of ApoE4 indicates the subject is afflicted with Alzheimer""s disease or at risk of developing Alzheimer""s disease. This basic finding has led to a number of developments in the Alzheimer""s disease field.
For example, U.S. Pat. No. 5,773,220 to S. DeKosy and M. Kamboh, assigned to the University of Pittsburgh, describes a method for screening for the risk of developing Alzheimer""s disease in a subject by detecting the presence or absence of the ApoE allele and the presence or absence of the alpha1-antichymotrypsin (ACT) allele. The presence of two ACT/A alleles, in conjunction with the presence of one or two ApoE4 alleles, is said to indicate an increased risk for Alzheimer""s disease.
In addition, U.S. Pat. No. 5,935,781 to J. Poirer, assigned to McGill University. This patent describes a method for the identification of human subjects responsive to cholinomimetic therapy. The method comprises determining the absence of apolipoprotein E4 (apoE4) alleles in a biological sample of the patient, where the absence of at least one apoE4 allele indicates a predisposition to respond to cholinomimetic therapy. Methods of administering cholinomimetics to such identified subjects are also described.
While the identification of ApoE4 as a risk factor for Alzheimer""s disease has led to a number of new developments in the field, AD remains a complex disease for which treatment is difficult and the ultimate prognosis is poor. Accordingly, there remains a need for new ways to screen for AD, classify patients for appropriate AD treatment, and treat AD.
A first aspect of the present invention is a method of screening (e.g., diagnosing or prognosing) a subject for risk of developing Alzheimer""s disease. The method comprises: (a) determining the presence of at least one ApoE4 allele in a subject, and (b) determining the presence or absence of decreased estrogen levels in said subject. The presence of at least one ApoE4 allele (and particularly two ApoE4 alleles) in combination with decreased estrogen levels in said subject indicating said subject is at greater risk of developing Alzheimer""s disease (e.g., as compared to subjects with at corresponding number of ApoE4 alleles, but who do not have decreased estrogen levels).
A second aspect of the present invention is a method for screening a subject for responsiveness to estrogen replacement therapy for the treatment of Alzheimer""s disease. The method comprises determining the presence of at least on ApoE4 allele in the subject. The presence of at least one apoE4 gene allele allele (and particularly two ApoE4 alleles) indicates that the subject will receive greater benefit from estrogen replacement therapy that a subject who does not carry at least one ApoE4 allele allele (and particularly two ApoE4 alleles). Alternatively stated, the presence of at least one ApoE4 allele indicates a predisposition, or potential, of that subject to beneficially respond to estrogen replacement therapy (e.g., a greater likelihood that that subject will beneficially respond to estrogen replacement therapy as compared to a subject that does not carry at least one ApoE4 allele).
A third aspect of the present invention is a method for treating a subject for Alzheimer""s disease. The method comprises: (a) determining the presence of at least one ApoE4 allele in said subject allele (and particularly two ApoE4 alleles); and then (b) administering estrogen replacement therapy to that subject (i.e., a subject carrying one or two ApoE4 alleles) in an Alzheimer""s disease treatment effective amount.
A fourth aspect of the present invention is a method of treating a human female subject for Alzheimer""s disease, where that subject carries at least one ApoE4 allele allele (and particularly two ApoE4 alleles). The method comprises administering estrogen replacement therapy to the subject in an Alzheimer""s disease treatment effective amount.
In a particularly preferred embodiment, the estrogen replacement therapy is initiated to a susceptible subject as described above prior to the onset of menopause, or at least concurrently with the onset of menopause, or is initiated concurrently with a hysterectomy. The object in this embodiment is to reduce, inhibit, or eliminate a gap in estrogen levels, or the time for which the subject is exposed to decreased estrogen levels, so that the risk of early neuronal cell death in that patient is reduced, and the time of onset of Alzheimer""s disease is delayed, and/or the progression of that disease is slowed.
A fifth aspect of the present invention is the use of an estrogen replacement therapy active agent for the preparation of a medicament for the treatment of Alzheimer""s disease.
The foregoing and other objects and aspects of the present invention are explained in detail in the drawings herein and the specification set forth below.